Bioinformatic prediction of putative conveyers of O-GlcNAc transferase intellectual disability

Abstract

Protein O-GlcNAcylation is a dynamic posttranslational modification that is catalyzed by the enzyme O-GlcNAc transferase (OGT) and is essential for neurodevelopment and postnatal neuronal function. Missense mutations in OGT segregate with a novel X-linked intellectual disability syndrome, the OGT congenital disorder of glycosylation (OGT-CDG). One hypothesis for the etiology of OGT-CDG is that loss of OGT activity leads to hypo-O-GlcNAcylation of as yet unidentified, specific neuronal proteins, affecting essential embryonic, and postnatal neurodevelopmental processes; however, the identity of these O-GlcNAcylated proteins is not known. Here, we used bioinformatic techniques to integrate sequence conservation, structural data, clinical data, and the available literature to identify 22 candidate proteins that convey OGT-CDG. We found using gene ontology and PANTHER database data that these candidate proteins are involved in diverse processes including Ras/MAPK signaling, translational repression, cytoskeletal dynamics, and chromatin remodeling. We also identify pathogenic missense variants at O-GlcNAcylation sites that segregate with intellectual disability. This work establishes a preliminary platform for the mechanistic dissection of the links between protein O-GlcNAcylation and neurodevelopment in OGT-CDG.